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首页> 外文期刊>Biochemical Pharmacology >Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy
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Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy

机译：糖尿病周围神经病发病机制中葡萄糖代谢，12 / 15-脂氧合酶和有丝分裂原激活的蛋白激酶的山梨醇途径之间的相互作用

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The interactions among multiple pathogenetic mechanisms of diabetic peripheral neuropathy largely remain unexplored. Increased activity of aldose reductase, the first enzyme of the sorbitol pathway, leads to accumulation of cytosolic Ca 2+, essentially required for 12/15-lipoxygenase activation. The latter, in turn, causes oxidative-nitrosative stress, an important trigger of mitogen activated protein kinase (MAPK) phosphorylation. This study therefore evaluated the interplay of aldose reductase, 12/15-lipoxygenase, and MAPKs in diabetic peripheral neuropathy. In experiment 1, male control and streptozotocin-diabetic mice were maintained with or without the aldose reductase inhibitor fidarestat, 16 mg kg -1 d -1, for 12 weeks. In experiment 2, male control and streptozotocin-diabetic wild-type (C57Bl6/J) and 12/15-lipoxygenase-deficient mice were used. Fidarestat treatment did not affect diabetes-induced increase in glucose concentrations, but normalized sorbitol and fructose concentrations (enzymatic spectrofluorometric assays) as well as 12(S)-hydroxyeicosatetraenoic concentration (ELISA), a measure of 12/15-lipoxygenase activity, in the sciatic nerve and spinal cord. 12/15-lipoxygenase expression in these two tissues (Western blot analysis) as well as dorsal root ganglia (immunohistochemistry) was similarly elevated in untreated and fidarestat-treated diabetic mice. 12/15-Lipoxygenase gene deficiency prevented diabetes-associated p38 MAPK and ERK, but not SAPK/JNK, activation in the sciatic nerve (Western blot analysis) and all three MAPK activation in the dorsal root ganglia (immunohistochemistry). In contrast, spinal cord p38 MAPK, ERK, and SAPK/JNK were similarly activated in diabetic wild-type and 12/15-lipoxygenase -/- mice. These findings identify the nature and tissue specificity of interactions among three major mechanisms of diabetic peripheral neuropathy, and suggest that combination treatments, rather than monotherapies, can sometimes be an optimal choice for its management.
机译：糖尿病周围神经病的多种致病机制之间的相互作用在很大程度上尚待探索。醛糖还原酶（山梨醇途径的第一个酶）的活性增加导致胞质Ca 2+积累，这是12 / 15-脂氧合酶激活所必需的。后者反过来会引起氧化亚硝基应激，这是促分裂原活化蛋白激酶（MAPK）磷酸化的重要触发因素。因此，本研究评估了糖尿病周围神经病中醛糖还原酶，12 / 15-脂加氧酶和MAPK的相互作用。在实验1中，雄性对照和链脲佐菌素-糖尿病小鼠在有或没有醛糖还原酶抑制剂非达司他（fidarestat）16 mg kg -1 d -1的情况下维持12周。在实验2中，使用了雄性对照和链脲佐菌素-糖尿病野生型（C57B16 / J）和12 / 15-脂氧合酶缺陷型小鼠。 Fidarestat治疗不会影响糖尿病引起的葡萄糖浓度增加，但会影响正常的山梨糖醇和果糖浓度（酶促荧光分光光度法）以及12（S）-羟基二十碳四烯酸浓度（ELISA）（一种测量12 / 15-脂氧合酶活性的方法）坐骨神经和脊髓。在未经治疗和非达司他治疗的糖尿病小鼠中，这两个组织中的12 / 15-脂氧合酶表达（Western blot分析）以及背根神经节（免疫组织化学）也同样升高。 12 / 15-Lipoxygenase基因缺陷可预防糖尿病相关的p38 MAPK和ERK，但不能阻止SAPK / JNK，坐骨神经激活（Western blot分析）以及背根神经节的所有三个MAPK激活（免疫组织化学）。相反，在糖尿病野生型和12 / 15-脂加氧酶-/-小鼠中，脊髓p38 MAPK，ERK和SAPK / JNK被类似地激活。这些发现确定了糖尿病周围神经病变的三种主要机制之间相互作用的性质和组织特异性，并表明联合治疗而非单一疗法有时可能是其治疗的最佳选择。

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